The candidate's overall career goal is to establish an independent research program devoted to investigating cellular mechanisms of proteinuric nephropathies, with an emphasis on diabetic nephropathy (DN). Currently, DN is the leading cause of end stage renal disease in the United States. Proteinuria is an independent risk factor critical to pathogenesis and progression of renal function loss. Regardless of disease origin, renal tubule function is critical to the progression of renal damage and development of renal failure. The precise molecular mechanisms and targets of proteinuria and hyperglycemia causing tubule damage in DN remain unclear. This emphasizes the health-related importance for discovery of novel regulatory events as potential therapeutic targets. The endoplasmic reticulum (ER) stress response induced by accumulation of misfolded proteins in the ER, is a mechanism elicited by cells to alleviate stress, through induction of specific genes. Unresolved ER stress response leads to ER stress-induced apoptosis. Initial studies from our laboratory demonstrate induction of ER stress and ER stress-induced apoptosis in tubules of proteinuric diabetic mice. This suggests the hypothesis that ER stress is pathogenic in renal tubule damage in DN. This project will define the role of proteinuria and hyperglycemia alone and in combination to tubule ER stress and apoptosis in a transgenic mouse model of type I diabetes. Next, cell signaling events mediating tubule ER stress and apoptosis induction in DN will be examined. To accomplish this, the candidate will be trained in development of speed congenic transgenic mice. In addition the candidate will be trained in protein purification, mass spectrometry and informatic techniques to define interactions in protein complexes mediating ER stress. Finally, the candidate will receive training in advanced molecular biology techniques to define the specific role of proteins involved in stress response to tubule cell function. The combination of training obtained during this award coupled to the identification of molecular events mediating tubule damage in DN, will enable the candidate with resources to continue and expand research pertaining to DN. PUBLIC HEALTH RELEVANCE: Currently, DN is the leading cause of end stage renal disease in the United States. Proteinuria is an independent risk factor critical to pathogenesis and progression of renal function loss. The precise molecular mechanisms and targets of proteinuria and hyperglycemia causing tubule damage in DN remain unclear. This emphasizes the importance for discovery of novel regulatory events as potential therapeutic targets.